The present invention relates to a process for the preparation of the compounds of the formulae 
where R1-R4 are, independently from each other, hydrogen, halogen, hydroxy, amino, nitro, lower-alkyl-sulfonylamido, or acetamido; R5-R8 are, independently from each other hydrogen, lower-alkyl, halogen, trifluoromethyl or lower-alkoxy; and their pharmaceutically acceptable acid addition salts, especially the compounds formula I-a. These compounds are active as NMDA (N-methyl-D-aspartate) receptor-subtype selective blockers.
Under pathological conditions of acute and chronic forms of neurodegeneration overactivation of NMDA receptors is a key event for triggering neuronal cell death. NMDA receptors are composed of members from two subunit families, namely NR-1 (8 different splice variants) and NR-2 (A to D) originating from different genes. Members from the two subunit families show a distinct distribution in different brain areas. Heteromeric combinations of NR-1 members with different NR-2 subunits result in NMDA receptors displaying different pharmacological properties. Possible therapeutic indications for NMDA receptor subtype specific blockers such as the compounds of formula I include acute forms of neurodegeneration caused, e.g., by stroke or brain trauma; chronic forms of neurodegeneration such as Alzheimer""s disease, Parkinson""s disease, Huntington""s disease or ALS (amyotrophic lateral sclerosis); neurodegeneration associated with bacterial or viral infections, diseases such as schizophrenia, anxiety and depression and acute/chronic pain. Ethanesulfonyl-piperidine derivatives that are NMDA (N-methyl-D-aspartate)-receptor-subtype selective blockers also have a key function in modulating neuronal activity and plasticity and are key players in mediating processes underlying development of CNS including learning and memory formation and function.
The compounds of formula I and their pharmaceutically acceptable salts can be prepared by methods known in the art, e.g. in WO 95/25721, for example by processes described below, which comprises
a) reacting a compound of formula 
with a compound of formula 
to a compound of formula 
wherein the substituents are as defined above and X signifies a leaving group, and, if desired,
b) converting the compound of formula I obtained into a pharmaceutically acceptable acid addition salt, and, if desired,
c) converting a racemic mixture at the stage of formula III or at the stage of formula I into enantiomeric compounds III-a, III-b 
or I-a, I-b respectively, thus obtaining optically pure compounds. However, the above processes usually lead to yields of 10% or less of the desired compound due to the poor efficiency of the methods employed, i.e. resolution by crystallization of diasteromeric salts.
It has now been found that the compounds of formula I-a and I-b can be prepared more effectively and with considerably higher yield if manufactured according to reaction scheme 1.
All starting materials are known compounds or may be prepared by methods known in the art. 
wherein
R1-R8 are as defined above;
R9 is an amino protecting group, preferably benzyl;
R10 and R10xe2x80x2 are independently a carboxylic acid protecting group;
Y and X represent independently a leaving group; and
AZ signifies a mineral acid from the group of HBF4, H2SO4, HPF6, HBr, HI, HCl, HSbF6 or HClO4, or a strong organic acid from the group of C1-8-alkylSO3H, picric acid, formic acid, a lower alkylcarboxylic acid such as e.g. acetic acid, propionic acid or trifluoroacetic acid, or a dicarboxylic acid, such as e.g. oxalic acid, succinic acid, maleic acid, tartaric acid or phthalic acid.
Step 5 (asymmetric hydrogenation) and step 6 (deprotection of the ring nitrogen) can be inverted (Step 6* and step 5*).
Accordingly, this invention is directed to a process (Process A) for the preparation of compounds of formulae 
wherein R1-R4 are, independently from each other, hydrogen, halogen, hydroxy, amino, nitro, lower-alkyl-sulfonylamido, or acetamido; R5-R8 are, independently from each, other hydrogen, lower-alkyl, halogen, trifluoromethyl or lower-alkoxy; and their pharmaceutically acceptable acid addition salts; which process comprises
a) reacting a protected amino acid ester (1) 
with a 4-substituted butyric acid derivative (2) 
wherein R9 is an amino protecting group, preferably benzyl; R10 and R10xe2x80x2 are independently a carboxylic acid protecting group; and Y represents a leaving group; in the presence of a base to obtain the protected alkoxycarbonylmethyl amino butyric acid derivative (3);
b) cyclising the protected alkoxycarbonylmethyl amino butyric acid derivative (3) 
wherein the symbols are as defined above to obtain the protected alkyl 3-oxo-piperidine carboxylate salt(4);
c) benzylating the protected alkyl 3-oxo-piperidine carboxylate salt (4) 
wherein AZ signifies a mineral acid or a strong organic acid to obtain the benzylated protected alkyl 3-oxo-piperidine carboxylate (5);
d) decarboxylating the benzylated protected alkyl 3-oxo-piperidine carboxylate (5) 
wherein the symbols are as defined above; in presence of a strong acid to obtain the salt of formula (6);
e) asymmetrically hydrogenating the salt of formula (6) 
wherein R9 is an amino protecting group; in presence of a ruthenium complex with a chiral diphosphine ligand and a chiral diamine, wherein the diphosphine has an (S) configuration and the diamine has an (R,R) configuration or the diphosphine has an (R) configuration and the diamine has an (S,S) configuration, and an organic or inorganic base, to obtain the compound of formula (7a) or (7b); and deprotecting the compound of formula (7a) or (7b) 
wherein the symbols are as defined above; or
asymmetrically hydrogenating the salt of formula (6bis) 
in presence of a ruthenium complex with a chiral diphosphine ligand and a chiral diamine, wherein the diphosphine has an (S) configuration and the diamine has an (R,R) configuration or the diphosphine has an (R) configuration and the diamine has an (S,S) configuration, and a organic or an inorganic base, to obtain the piperidine derivative of formula III-a or III-b; and
f) reacting the piperidine derivative of formula III-a or III-b 
wherein the symbols are as defined above; with the reactive vinyl sulfone intermediate 
which is obtained by treating the sulfone derivative of formula II 
wherein R1-R4 are as defined above; and X is a leaving group; with a base; in the presence of a base to form the desired compound of formula I-a or I-b.
The above process provides compounds of formulae I-a and I-b, which are the cis compounds of the compound of formula I. By this process, trans compounds of formula I are excluded.
The above process is particularly preferred for the preparation of compounds of formula I-a. In this preferred process, the ruthenium complex of step e), the diphosphine has an (S) configuration and the diamine has an (R,R) configuration.
This invention is also directed to Process B, which is the above process for the preparation of compounds of formulae 
wherein R1-R4 are, independently from each other, hydrogen, halogen, hydroxy, amino, nitro, lower-alkyl-sulfonylamido, or acetamido; R5-R8 are, independently from each, other hydrogen, lower-alkyl, halogen, trifluoromethyl or lower-alkoxy; and their pharmaceutically acceptable acid addition salts; which process comprises
a) deprotonating a substituted thiophenol derivative of formula (8) 
wherein the symbols are as defined above; in presence of a strong inorganic or organic base and subsequently reacting it with 2-haloethanol to obtain the thioether of formula (9);
b) oxidizing the thioether of formula (9) 
wherein the symbols are as defined above; in presence of an oxidative agent to obtain the sulfone derivative of formula (10);
c) replacing the hydroxy group of the sulfone derivative of formula (10) 
wherein the symbols are as defined above; by a halogen atom in the presence of pyridine in dichloromethane to obtain the sulfone derivative of formula II; and
d) treating the sulfone derivative of formula II 
wherein R1-R4 are as defined above; and X is halogen; with a base to form the corresponding reactive vinyl sulfone intermediate of formula II* 
which is then reacted with the piperidine derivative of formula 
wherein the symbols are as defined above in presence of a base to obtain the compounds of formulae I-a or I-b.
This invention is also directed to compounds of formula (6) and (6 bis) 
wherein R1-R4 are, independently from each other, hydrogen, halogen, hydroxy, amino, nitro, lower-alkyl-sulfonylamido, or acetamido;R5-R8 are, independently from each, other hydrogen, lower-alkyl, halogen, trifluoromethyl or lower-alkoxy and their pharmaceutically acceptable acid addition salts.
In more detail, this invention is also directed to processes which are part of Process A or Process B, for instance Process C, a process for the preparation of compounds of formula 
wherein R1-R4 are, independently from each other, hydrogen, halogen, hydroxy, amino, nitro, lower-alkyl-sulfonylamido, or acetamido; R5-R8 are, independently from each other, hydrogen, lower-alkyl, halogen, trifluoromethyl or lower-alkoxy; R9 is an amino protecting group; AZ signifies a mineral acid or a strong organic acid; which process comprises
a) reacting a protected amino acid ester (1) 
with a 4-substituted butyric acid derivative (2) 
wherein
R9 is an amino protecting group, preferably benzyl;
R10 and R10xe2x80x2 are independently a carboxylic acid protecting group; and Y represents a leaving group; in the presence of a base; to obtain the protected alkoxycarbonylmethylamino butyric acid derivative (3);
b) cyclising the protected alkoxycarbonylmethyl amino butyric acid derivative (3) 
wherein the symbols are as defined above to obtain the protected alkyl-3-oxo-piperidine caboxylate salt (4);
c) benzylating the protected alkyl 3-oxo-piperidine carboxylate salt(4) 
wherein AZ signifies a mineral acid or a strong organic acid to obtain the benzylatedprotected alkyl-3-oxo-piperidine carboxylate (5);
d) decarboxylating the benzylated protected alkyl 3-oxo-piperidine carboxylate (5) 
wherein the symbols are as defined above; in presence of a strong acid to obtain the compound of formula (6); and, to obtain the compound of formula (6bis), deprotecting compound of formula (6).
This invention is also directed to Process D, a process for the preparation of compounds of formula 
wherein R1-R4 are, independently from each other, hydrogen, halogen, hydroxy, amino, nitro, lower-alkyl-sulfonylamido, or acetamido; R5-R8 are, independently from each, other hydrogen, lower-alkyl, halogen, trifluoromethyl or lower-alkoxy; and their pharmaceutically acceptable acid addition salts, which process comprises asymmetrically hydrogenating a salt of formula (6) 
wherein R9 is an amino protecting group; in presence of a ruthenium complex with a chiral diphosphine ligand and a chiral diamine wherein the diphosphine has an (S) configuration and the diamine has an (R,R) configuration or the diphosphine has an (R) configuration and the diamine has an (S,S) configuration and an organic or inorganic base to obtain the compound of formula (7a) or (7b);
and deprotecting the compound of formula (7a) or (7b) 
wherein the symbols are as defined above; or
deprotecting the compound of formula (6); and asymmetrically hydrogenating the salt of formula (6bis) 
in presence of a ruthenium complex with a chiral diphosphine ligand and a chiral diamine wherein the diphosphine has an (S) configuration and the diamine has an (R,R) configuration or the diphosphine has an (R) configuration and the diamine has an (S,S) configuration and an organic or inorganic base to obtain the piperidine derivative of formula III-a or III-b;
In any relevant process of this invention where asymmetric hydrogenation occurs, for example Process A or D, it is possible to direct this process to the preparation of compounds of formula III-a by using a ruthenium complex where the diphosphine has an (S) configuration and the diamine has an (R,R) configuration.
Similarly, in any relevant process of this invention, for example Process A, and especially D, the ruthenium complex used for the asymmetric hydrogenation is preferably a complex of formula IV
Ru(E)2(L)(A) 
wherein E is a halogen atom; L is a chiral diphosphine ligand; and A is a chiral diamine.
In this complex, the chiral diphosphine ligands are ligands of formulae 
and R11 and R12 are independently from each other alkyl, cycloalkyl, optionally substituted phenyl or a heterocyclic ring, and the chiral diamines are compounds of formulae 
wherein tBu signifies tert.-butyl, Me is methyl and Cy stands for cyclohexane.
In any relevant process of this invention, for example Process A, D, and the process immediately above, preferably R11 and R12 are independently from each other 
where iPr is iso-propyl and tBu is tert.-butyl. Also, it is preferred that the chiral diamine is a compound of formula V.
In any relevant process of this invention, for example Process A or D, and especially the processes of the above two paragraphs, the amount of chiral diamine used in the reaction is preferably from about 0.5 to about 2.5 equivalents based on the Ru-complex Similarly, the organic or inorganic base is preferably present in the amount of about 1.0 to about 0.001 mol equivalents, and more preferably 0.05-0.2 mol equivalents, with respect to the substrate in addition to the about 1 mol equivalent of organic or inorganic base present for the neutralization of the acid salt of the substrate (6) or (6 bis). Preferably both these conditions exist in any of these processes.
A preferred organic or inorganic base for any of the above-described processes is potassium tert.-butylate.
This invention is also directed to a process of Process B above, for the preparation of compounds of formula 
wherein R1-R4 are, independently from each other, hydrogen, halogen, hydroxy, amino, nitro, lower-alkyl-sulfonylamido, or acetamido; and Xxe2x80x2 is halogen; which process comprises
a) deprotonating a substituted thiophenol derivative of formula (8) 
wherein the symbols are as defined above, in presence of a strong inorganic or organic base and subsequently reacting it with 2-haloethanol to obtain the thioether of formula (9);
b) oxidizing the thioether of formula (9) 
wherein the symbols are as defined above; in presence of an oxidative agent to obtain the sulfone derivative of formula (10);
c) replacing the hydroxy group of the sulfone derivative of formula (10) 
wherein the symbols are as defined above, by a halogen atom in the presence of pyridine in dichloromethane to obtain the compound of formula II.
The processes of this invention involve several key steps such as new methods for the preparation of the intermediates of formula II 
and of formula III, especially by a new approach for the enantioselective preparation of the intermediate of formula III, i.e. of the intermediates of formulae 
wherein the symbols are as defined above.
The processes of this invention for the preparation of the intermediate III-a and III-b involve two key reactions:
a) A process of this invention for the preparation of the compound of formula (4) or of a salt thereof starting with a protected glycine (1) and a butyric acid derivative (2). The process of this inventions considerably shorter and gives much higher yields than the conventionally used processes described in Helv. Chim. Acta, 1954, 20, 178; J. Am. Chem. Soc., 1948, 71, 896 or in J. Chem. Soc. Perkin Trans. 1, 1998, 3673. 
wherein
Y signifies a leaving group;
R10 and R10xe2x80x2 signify independently a carboxylic acid protecting group;
R9 signifies an amino protecting group, preferably benzyl; and
AZ is as defined above.
The compound of formula (4) is then transformed according to standard procedures as depicted in reaction scheme 1, by benzylation in position 4 of the piperidine ring to form a compound of formula (5) (step 3). Subsequent decarboxylation and formation of the stable salt yields a compound of formula (6) (step 4).
b) Both the free base of formula (6 and 6bis) and its salts can be submitted to the asymmetric hydrogenation reaction, which proceeds with concomitant dynamic-kinetic resolution. However, due to the limited stability of the free base, according to the invention a salt thereof is preferentially submitted to the asymmetric hydrogenation reaction in the presence of a homogeneous chiral catalyst (i.e. and (S,S) or (R,R) catalyst), a chiral diamine and an organic or an inorganic base (step 5 and step 5*, respectively). 
where R9 is an amino protecting group, preferably benzyl, AZ and R5-R8 are as defined above.
The amino protecting group R9 may be removed in step 6* before submitting the unprotected compound of formula (6bis) to the asymmetric hydrogenation (step 5*): 
wherein AZ and R5-R8 are as defined above.
Furthermore, the invention relates to a process for the preparation of intermediates of formula (II) which are conventionally prepared starting from substituted thiophenol (8) and 2-bromoethanol and subsequent transformation with SOCl2 to obtain the highly mutagenic and unstable substituted (2-chloroethylsulfanyl)-benzene. The new and enhanced process for the preparation of intermediates of formula (II) avoids the presence of said highly mutagenic and unstable compound: 
wherein X is a leaving group, preferably a halogen, and R1-R4 are as defined above.
The invention is thus concerned with processes for the preparation of chiral compounds of formula I-a and I-b, respectively, which comprise:
Step 1, reacting a protected amino acid ester (1) with a 4-substituted butyric acid derivative (2) in the presence of a base to form an N-protected alkyloxycarbonylmethyl-amino-butyric acid derivative (3); preferred bases for the present reaction are organic bases such as triethylamine, ethyl-diisopropylamine, or inorganic bases such as K2CO3 or Na2CO3. The reaction is carried out in an inert polar solvent preferably in dimethylformamide (DMF), dioxane or acetonitrile. The reaction is carried out at a temperature between 0xc2x0 C. and 120xc2x0 C., preferably at a temperature between 40xc2x0 C. and 80xc2x0 C.
Step 2, cyclising the protected alkoxycarbonylmethyl amino butyric acid derivative (3) in a Dieckmann condensation to yield protected alkyl 3-oxo-piperidine carboxylate (4) which is isolated as a salt from a mineral acid or a strong organic acid, preferably as the hydrochloride salt. The reaction is preferably carried out in an apolar aromatic solvent such as toluene at a temperature of about 40xc2x0 C. to about 120xc2x0 C., preferably at a temperature of about 85xc2x0 C.
Step 3, benzylating the protected alkyl 3-oxo-piperidine carboxylate (4) salt. This reaction is well known in the art and can be carried out for example in the presence of a base and an appropriate solvent, such as for example with potassium-tert.-butoxyde in tetrahydrofuran (THF), with NaH in THF, NaOC2H5 in ethanol, K2CO3 in THF or in dimethylformamide (DMF).
Step 4, decarboxylation of the benzylated N-protected alkyl 3-oxo-piperidine carboxylate (5). The decarboxylation reaction is carried out by methods known in the art, for example by heating in the presence of a strong acid such hydrochloric acid, sulfuric acid and the like. The resulting salt is identified by formula (6) or (6bis).
Step 5 and 5*, asymmetric hydrogenation of the salt of formula (6) or (6bis) in presence of a ruthenium complex with a chiral diphosphine ligand, a chiral diamine and an organic or an inorganic base.
Typical of Steps 5 and 5* is the fact that the substrates (6) and (6bis) are racemic compounds which contain weakly acidic protons on the chiral carbon atoms. During the asymmetric hydrogenation the chiral catalyst converts at first only one enantiomer of (6) or (6bis). In the mean time, due to the configurational lability of the chiral center, the other enantiomer is racemized in situ by the base. Since the desired enantiomer of (6) and (6bis) to be hydrogenated is generated continuously from the undesired one, finally 100% yield of the single desired enantiomer of the products (7a) or (III-a) or of (7b) or (III-b), depending on the chirality of the catalyst selected, can be obtained.
It has been found that the salt of the piperidine derivative of formula (6) is stable and can be hydrogenated in high optical and chemical yields by the process according to the invention. The hydrogenation may also be performed with the salt of the unprotected piperidine derivative of formula (6bis).
The asymmetric hydrogenation is carried out in presence of a ruthenium phosphine complex represented by the formula
Ru(E)2(L) (A) xe2x80x83xe2x80x83IV 
wherein
E is a halogen atom;
L is a chiral diphosphine ligand; and
A is a chiral diamine.
Complexes of type IV can be specifically prepared, isolated and characterized in analogy to the methods described in Angew. Chem. Int. Ed. 1998, 37, 1703-1707 and in the references cited therein, or can be prepared xe2x80x9cin situxe2x80x9d from components as described in above mentioned reference, and be employed without intermediate isolation in the catalytic asymmetric hydrogenation. When the complexes of type IV are prepared in situ, the amount of chiral diphosphine ligand (L) used in the reaction can vary from 0.5 to 2.5 equivalents relative to ruthenium, preferably from 0.8 to 1.2 equivalents. Analogously the amount of chiral diamine can vary from 0.5 to 2.5 equivalents based on the amount of the ruthenium-complex, preferably 1 to 2 equivalents.
Suitable chiral diphosphine ligands are known in the art. Such ligands are for example atropisomeric biphenyl-phosphine or binaphthyl-phosphine derivatives. Further ligands which may be useful in the present hydrogenation are 1,2-bis(2,5-dimethylphospholano)benzene as described in U.S. Pat. No. 5,171,892; 1-[2-(diphenylphosphino)ferrocenyl]ethyl-di-tert.-butyl-phosphine as described in EP 0 564 406; 1-[2-(di-(4-trifluoromethyl)phenyl)-phosphino)ferrocenyl]ethyl-di-phenyl-phosphine as in EP 0 646 590; 4,12-bis(diphenylphosphino)-[2.2]paracyclophane (Tetrahedron Letters 1998, 39, 4441-4444); 4,4xe2x80x2-Bisdiphenylphosphine-2,2xe2x80x2,5,5xe2x80x2-tetramethyl-3,3xe2x80x2-dithiophene (WO 96/01831); 2,2-Bis-(diphenylphosphinyl)-3,3xe2x80x2-dibenzo [b]thiophene (WO 96/01831); (2R,2xe2x80x2R)-Bis(diphenylphosphino)-(1R,1xe2x80x2R)-dicyclopentane and enantiomer (WO 97/47633); 1,2-Bis{(1R,2R,4R,5R)-2,5-bis-isopropyl-8-phenylphosphabicyclo [2.2.1]heptyl}benzene and enantiomer (WO 97/47633); 2,2xe2x80x2,3,3xe2x80x2-Tetraphenyl-4,4xe2x80x2,5,5xe2x80x2-tetramethyl-6,6xe2x80x2-bis-phosphanorborna-2,5-dienyl (Chem Eur Journal 1997,3, 1365-1369); (xcex1R-xcex1Rxe2x80x2)-2,2xe2x80x2-Bis((xcex1-N,N-dimethylaminopropyl)-(S,S)-1,1xe2x80x2-bis(diphenylphosphino)ferrocene and enantiomer (Tetrahedron: Asymmetry 1999,10, 375-384); and ((5,6),(5xe2x80x2,6xe2x80x2)-Bis(methylenedioxy)biphenyl-2,2xe2x80x2-diyl)bis(diphenylphosphine) (EP 850945).
Preferably chiral diphosphine ligands of the formulae depicted below are used 
wherein
R11 and R12 are independently from each other alkyl, cycloalkyl, optionally substituted phenyl or a heterocyclic ring.
Preferred residue R11 and R12 are 
Especially preferred chiral diphosphine ligands are 
(S)- or (R)-(3,5-Xyl)-MeOBIPHEP BIPHEMP 
(S)- or (R)-(3,5-iPr)-MeOBIPHEP
Above-mentioned diphosphine ligands are known in the art and can be prepared for example as described in EP 0 398 132 and WO-92/16535 (MeOBIPHEP; 3,5-iPr-MeOBIPHEP), in EP 0 104 375 (BIPHEMP) and in EP 0 580 331 (BINAP).
In order to obtain high yields of the cis-configured product of formula III-a or III-b, in high optical purity it is essential that the reaction be carried out in the presence of a chiral diamine which is in xe2x80x9cunlikexe2x80x9d configuration to the chiral complex, i.e. it is important that the diphosphine is (S) and the diamine is (R,R) or that the diphosphine is (R) and the diamine is (S,S). In the former case (S diphosphine and R,R diamine), the cis isomer produced is III-a, in the latter case(R diphosphine and S,S diamine) the cis isomer produced is III-b. The reaction is carried out in presence of chiral diamines as depicted below: 
Further suitable chiral diamines are propane- and butanediamines. An especially preferred chiral diamine is DPEN (V), (R,R) or (S,S)-1,2-diphenylethylenediamine. The chiral diamines are commercially available or can be prepared according to known methods.
The hydrogenation is preferably carried out in an organic solvent which is inert under the reaction conditions. As such solvents there can be mentioned, in particular, lower alcohols such as e.g. methanol, ethanol or isopropanol, trifluoroethanol or mixtures of such alcohols with halogenated hydrocarbons such as methylene chloride, chloroform, hexafluorobenzene and the like or with ethers such as diethyl ether, tetrahydrofuran or dioxane. Preferred solvent for the reaction are lower alcohols, especially preferred is isopropanol. The reaction is carried out at a concentration of about 1 to 50%, ideally about 5 to 30%.
The substrate-to-catalyst molar ratio (S/C ratio) is 10-1,000,000, preferably 100-800,00. The hydrogenation is carried out at a pressure of 105-108 Pa, ideally at a pressure of about 105 to 107 Pa and at a temperature of about 0xc2x0 C. to about 50xc2x0 C., ideally at 20xc2x0 C. to 40xc2x0 C.
Preferred bases used in the asymmetric hydrogenation are for example inorganic or organic bases. Preferred inorganic bases are alkali or alkaline earth metal hydroxides, carbonates, hydrogenocarbonates, alcoholates or silanolates such as for example LiOH, LiOCH3, LiOC2H5, LiOCH(CH3)2, LiOC(CH3)3, NaOH, NaOCH3, NaOC2H5, NaOCH(CH3)2, NaOC(CH3)3, KOH, KOCH3, KOC2H5, KOCH(CH3)2, KOC(CH3)3, KOSi(CH3)3, or Cs2CO3 preferred inorganic bases are alcoholates, especially KOC(CH3)3. Preferred organic bases are tertiary amines such as triethylamine, ethyl-diisopropylamine, tripropylamine and the like.
The amount of organic or inorganic base present in the reaction is about 1.0 to about 0.001, preferably about 0.05 to about 0.2 mol equivalents with respect to the substrate in addition to 1 mol equivalent of organic or inorganic base which is necessary to neutralize the acid salt of the substrate of formula (6) or (6bis), respectively.
The asymmetric hydrogenation of step 5 can be carried out either batchwise or in a continuous manner.
Step 6, deprotection of the compound of formula (7a) or the isomer (7b) under standard conditions depending on the N protecting group, for example by hydrogenation of the N-benzylated compound in presence of Pd/C to form the unprotected amine III-a and III-b, respectively.
Step 6*, refers to the deprotection of the compound of formula (6) in analogy to step 6, to compound (6bis) which is then subsequently submitted to the asymmetric hydrogenation (step 5* discussed above).
Step 7, treating the sulfone intermediate of formula II with a base to form the corresponding vinyl sulfone derivative which is subsequently reacted with the piperidine derivative of formula III-a or III-b to the desired product of formula I-a or I-b, respectively. The reaction is carried out in presence of bases such as triethylamine in solvents such as CH2Cl2.
As already mentioned previously sulfones of formula II are usually prepared by halogenation of the hydroxy thioether of formula (9) to form the highly toxic and unstable chlorothioether which is then subsequently oxidized to form the intermediate of formula II. The invention now provides a new process to produce this intermediate of formula II, see Scheme 4 which avoids the formation of highly toxic intermediates. The process according to the invention consists of the following steps:
step a), a substituted thiophenyl derivative (8) is deprotonated in presence of a strong inorganic or organic base as defined above and subsequently reacted with 2-haloethanol to form the thioether of formula (9);
step b), oxidation of the thioether (9) in presence of an oxidative agent such as 3-chloroperbenzoic acid (MCPBA), H2O2/AcOH, KMnO4, tBuOOH, NMO/OsO4, or oxoneo to yield the corresponding sulfone of formula (10); and
step c), replacement of the hydroxy group of the sulfone derivative by a halogen atom e.g. with SOXxe2x80x22, wherein Xxe2x80x2 is halogen, e.g. chlorine, bromine or iodine in the presence of pyridine in dichloromethane.
The term xe2x80x9cpharmaceutically acceptable acid addition saltsxe2x80x9d embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, lactic acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulfonic acid and the like.
As used herein, the term xe2x80x9calkylxe2x80x9d refers to both straight and branched chain saturated hydrocarbon groups having 1 to 10 carbon atoms; whereas the term lower alkyl refers to both straight and branched chain saturated hydrocarbon groups having 1 to 5 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, tert.-butyl and the like. The term xe2x80x9clower alkoxyxe2x80x9d means a lower alkyl group as defined above, bonded through an oxygen atom. Examples are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy and the like.
The term xe2x80x9clower-alkyl-sulfonylamidoxe2x80x9d refers to sulfonamido groups substituted with xe2x80x9clower alkylxe2x80x9d groups as defined above.
The term xe2x80x9ccycloalkylxe2x80x9d refers to a cyclic hydrocarbon group having 3 to 7 carbon atoms. Such groups are for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
The term xe2x80x9coptionally substituted phenylxe2x80x9d refers to unsubstituted phenyl or mono, di- or trisubstituted phenyl groups with substituents such as lower alkyl, alkoxy groups or halogenated alkyl such as trifluoromethyl, pentafluoroethyl, or substituted with halogen, hydroxy, amino, dialkylamino or acetamido, or substituted with phenyl or trialkylsilyl and the like.
As used herein xe2x80x9cheterocyclic ringxe2x80x9d refers to 5 or 6-membered rings containing one or two hetero atoms chosen from O, S and N. Examples of preferred heterocyclic rings are furane, thiophene, pyrrole, pyridine and pyrimidine. The heterocyclic rings may be unsubstituted or substituted with substituents as defined for xe2x80x9csubstituted phenylxe2x80x9d.
As used herein the term xe2x80x9cleaving groupxe2x80x9d refers to conventionally used easily substituted functional groups such as halogen, e.g. chlorine, bromine or iodine, or organic acid residues such as sulfonic acid derivatives, e.g. p-toluene sulfonate, brosylate, methylsulfonate, triflate (trifluoromethylsulfonate) and the like.
Nucleophilic substitution of the leaving groups (steps 1 and 7) are carried out by methods known in the art, e.g. in inert organic solvents under basic conditions. xe2x80x9cInert organic solventsxe2x80x9d refers to polar solvents such as dimethylformamide (DMF), dimethylacetamide (DMA), dimethylsulfoxide (DMSO), or to alcohols such as methanol, ethanol or isopropanol, or to cyclic ethers such as dioxane or tetrahydrofurane (THF), or to halogenated hydrocarbons such as dichloromethane, or to aromatic hydrocarbons such as toluene, or to nitrites, such as acetonitrile, or to mixtures of the named solvents. As bases are used inorganic or organic bases. Preferred inorganic bases are alkali or alkaline earth metal hydroxides, carbonates, hydrogenocarbonates, alcoholates or silanolates. Preferred organic bases are tertiary amines such as triethylamine, ethyl-diisopropylamine, tripropylamine and the like.
The term xe2x80x9camino protecting groupxe2x80x9d refers in the scope of the present invention to groups such as those employed in peptide chemistry for example to benzyl, tert.-butoxycarbonyl, allyloxy carbonyl and the like; to a substituted alkoxycarbonyl group such as trichloroethoxycarbonyl etc.; to an optionally substituted aralkyloxycarbonyl group, for example, p-nitrobenzyloxycarbonyl or benzyloxycarbonyl; to an aralkyl group such as trityl or benzhydryl; to an alkanoyl group such as formyl or acetyl; to a halogen-alkanoyl group such as chloroacetyl, bromoacetyl, iodoacetyl or trifluoroacetyl; or to a silyl protective group such as the trimethylsilyl group. Especially preferred amino protecting are benzyl, tert.-butoxycarbonyl (BOC) and benzyloxycarbonyl (Z). For the hydrogenation step (step 5) to be highly enantioselective it is essential that the protected nitrogen is basic, therefore benzyl is an especially preferred protecting group.
The term xe2x80x9ccarboxylic acid protecting groupxe2x80x9d refers in the scope of the present invention to protecting groups conventionally used to replace the acidic proton of a carboxylic acid. Examples of such groups are described in Greene, T., Protective Groups in Organic Synthesis, Chapter 5, pp. 152-192 (John Wiley and Sons, Inc. 1981). Preferably these examples include methoxymethyl, methylthiomethyl, 2,2,2-trichloroethyl, 2-haloethyl, 2-(trimethylsilyl)ethyl, methyl, ethyl, isopropyl, tert.-butyl, allyl, benzyl, triphenylmethyl (trityl), benzhydryl, p-nitrobenzyl, p-methoxybenzyl, trimethylsilyl, triethylsilyl, tert.-butyldimethylsilyl, i-propyldimethylsilyl. Preferred are benzhydryl, tert.-butyl, p-nitrobenzyl, p-methoxybenzyl and allyl. Especially preferred carboxylic protecting groups are methyl, ethyl, tert. butyl or benzyl.
Suitable protecting groups and methods for their cleavage will be familiar to any person skilled in the art, although of course there can be used only those protecting groups which can be cleaved off by methods under the conditions of which other structural elements in the compounds are not affected.
The term xe2x80x9coxygen acid or complex acidxe2x80x9d signifies in the scope of the present invention acids from the group H2SO4, HClO4, HBrO4, HIO4, HNO3, H3PO4, CF3SO3H as well as halogen complexes with the elements boron, phosphorus, arsenic, antimony or bismuth. HClO4, CF3SO3H, HPF6, HBF4, HB(Ph)4, HB(3,5-(CF3)2xe2x80x94C6H3)4, HSbF6 and HAsF6 are preferred representatives with HSbF6 and HBF4 being most preferred.
The following abbreviations are used in the description of the examples: